# Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

Source: https://onco.cc/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/  
OnCo record `paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Most bowel cancers with a broken DNA spell-checker have not mutated the gene at all: they have switched it off chemically. Removing the chemical tag in the laboratory turned the gene, and the repair system, back on.

## Summary

Hypermethylation of the 5' CpG island of hMLH1 was found in the majority of sporadic primary colorectal cancers with microsatellite instability, and was often though not invariably associated with loss of hMLH1 protein expression. Methylation also occurred, less commonly, in microsatellite-stable tumours and in unstable tumours with known mismatch repair gene mutations; no hypermethylation of hMSH2 was found. In cell lines with microsatellite instability, reversal of methylation with 5-aza-2'-deoxycytidine restored hMLH1 protein expression and mismatch repair capacity.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Proceedings of the National Academy of Sciences
- Year: 1998
- DOI: 10.1073/pnas.95.12.6870
- Authors: Herman JG, Umar A, Polyak K, et al.
- Findings: hMLH1 promoter hypermethylation in the majority of sporadic microsatellite-unstable colorectal cancers.; Demethylation restored hMLH1 protein and mismatch repair capacity in deficient cell lines.
- What it means: It established the epigenetic route to mismatch repair deficiency, which is why an MLH1-deficient tumour is tested for MLH1 methylation or BRAF V600E before a family is told it may have Lynch syndrome.
- Caveats: Methylation assays of the era were less quantitative than today's.; The threshold that counts as promoter methylation varies between laboratories.

## Sources

- Herman et al., PNAS 1998: hMLH1 promoter hypermethylation in sporadic colorectal carcinoma: https://doi.org/10.1073/pnas.95.12.6870
- PubMed: https://pubmed.ncbi.nlm.nih.gov/9618505/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [MSI and mismatch-repair testing](https://onco.cc/technologies/msi-mmr-testing/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [MLH1](https://onco.cc/targets/mlh1/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/)
- terms: [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Kenneth W. Kinzler](https://onco.cc/people/kenneth-kinzler/), [Stephen B. Baylin](https://onco.cc/people/stephen-baylin/)
- journals: [Proceedings of the National Academy of Sciences](https://onco.cc/journals/pnas/)
- biomarkers: [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/)

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